Medicament containing cilansetron for the treatment of non-obstipative male irritable bowel syndrome patients

ABSTRACT

The present invention relates to the use of cilansetron for the treatment of non-obstipative male IBS patients.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional PatentApplication No. 60/220,848, filed Jul. 26, 2000. Convention priority isalso claimed based on Federal Republic of Germany Patent ApplicationNos. DE 100 36 645.7, filed Jul. 26, 2001 and DE 101 23 447.3, filed May14, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to a novel medicinal use ofcilansetron or the acid addition salts thereof.

[0003] Cilansetron is a 5HT₃-receptor antagonist which falls within thescope of European Patent No. EP 297,651 B1 and has the chemical name(R)-(−)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-one.

[0004] The use of, inter alia, cilansetron for the production ofpharmaceutical preparations for the treatment of functional disturbancesin the lower intestinal tract in larger mammals and humans which involveincreased sensitivity to pain and/or abnormally accelerated stoolpassage in the colon region is already known from European Patent No. EP601,345 B1. The functional disturbances which can be treated, interalia, by cilansetron also include, for example, “irritable bowelsyndrome” (=IBS), in particular in conjunction with abnormallyaccelerated passage of the stool through the colon.

[0005] In International Patent Application Publication No. WO 99/17755,5HT₃-receptor antagonists are described which are particularlywell-suited for the treatment of non-obstipative (=diarrhea-predominantIBS patient group; in contrast to the obstipation-predominant IBSpatient group) female IBS patients. Alosetron is cited as an example inWO 99/17755. In clinical tests, alosetron exhibited significantly bettereffectiveness on female IBS patients, compared with the effectiveness onmale IBS patients. On male test subjects treated with alosetron, nosignificant improvement in condition compared with the placebo group wasnoted in these clinical tests. In one embodiment of said application no.WO 99/17755, cilansetron also is mentioned among other substances ascoming within the scope of the disclosure.

SUMMARY OF THE INVENTION

[0006] It has now surprisingly been discovered that cilansetron isequally suitable for the treatment of non-obstipative male and femalepatients suffering from irritable bowel syndrome (=IBS).

[0007] The invention therefore relates to the use of cilansetron or thepharmacologically acceptable acid addition salts and/or solvates thereoffor the production of pharmaceutical preparations for the treatmentand/or prophylaxis of irritable bowel syndrome (IBS) in non-obstipativemale patients.

[0008] IBS designates a group of symptoms, accompanied by pain and/or afeeling of unwellness in the lower abdomen and altered intestinalactivity, such as diarrhea, obstipation (=constipation), or alternatelydiarrhea and obstipation. Since it has hitherto not been possible togive any clearly tangible physiological or other organic results as acause of IBS, medical diagnosis of this illness is usually based on theabsence or presence of a number of symptoms, which are generallyregarded as typical of IBS and are recorded for example in the “RomeCriteria” (cf. W. G. Thompson et al., Gastroent. Int. 2 (1989) 92-95; W.G. Thompson et al., Gut 45/II (1999) II 43-II 47; W. G. Thompson, Lancet341 (1993) 1569-1572).

[0009] According to the invention, cilansetron may preferably be used inthe form of cilansetron hydrochloride. Usually, cilansetronhydrochloride monohydrate is used. Further pharmacologically acceptableacid addition salts of cilansetron are known from EP 0 297 651 B1.

[0010] Clinical test data prove the surprising suitability ofcilansetron for the treatment of non-obstipative IBS patients of boththe male and the female sex.

[0011] The effect of cilansetron on non-obstipative IBS patients of bothsexes was investigated in a 12-week placebo-controlled clinicaldouble-blind study with randomized selection and parallel test groups.Within the scope of the study, those IBS patients were regarded asnon-obstipative patients whose symptoms met the “Rome Criteria” (seeabove) and the nature and frequency of whose stools met the followingcriteria:

[0012] i)<25% IBS events adversely affected by obstipation.

[0013] ii) Characterised as non-obstipative in accordance with the “RomeCriteria” (see above, people who did not have <3 bowel movements perweek and/or whose stools were not hard/lumpy in nature).

[0014] iii) <4 days (in succession or not in succession) without bowelmovement over a two-week observation period (=“run-in period”).

[0015] iv) Average nature of stools >4 (corresponding to the “Bristolstool scale”) over a two-week observation period.

[0016] Likewise, those patients were included in the study who responded“No” to the question about pain/feeling of unwellness in the lowerabdomen only in ≦50% of the cases or who judged their pain/feeling ofunwellness in the lower abdomen as “restrictive” for <2 times over atwo-week observation period.

[0017] Cilansetron was used in doses of 1, 2, 8 and 16 mg. The patientswere checked weekly for “adequate alleviation” (=primary effectivenessparameter) of their IBS symptoms (stomach pains such as pains in theabdomen, abnormal bowel activity). Stomach pains such as pains in theabdomen, nature of the stools and stool frequency were rated daily bythe patients (=secondary effectiveness parameter).

[0018] In a provisional result of the double-blind study, the data of atotal of 454 patients (297 female patients and 157 male patients) wereevaluated and plotted in the table below. Corresponding to the criteriaon which the clinical double-blind study was based, in both patientsubgroups of male IBS patients and female IBS patients the success ratesrelating to the “adequate alleviation” of the IBS symptoms as set forthin the table below were noted: TABLE Cilansetron (mg TID) Success rate[%] Placebo 1 2 8 16 Male patients 30.0 51.3 63.0 56.3 58.6 Femalepatients 41.8 69.6 60.3 56.9 61.4

[0019] The “primary effectiveness parameter” corresponds to the successrate (=“responder rate”) to the question, which was put weekly to thepatients, as to whether they had experienced “adequate alleviation” oftheir IBS symptoms (pain/feeling of unwellness in the lower abdomen,abnormal bowel activity) during the course of the previous week. A“responder” is regarded as a patient who was treated for at least fourweeks and who responded “Yes” to the question posed of whether “adequatealleviation” of his/her IBS symptoms had occurred for at least half ofhis/her treatment period.

[0020] At the end of the double-blind study, the data of a total of 471patients (308 female patients and 163 male patients) were evaluated. Thefinal success rates were 40% for the placebo group, 62% for the dose 1mg cilansetron (TID), 53% for the dose 2 mg cilansetron (TID), 55% forthe dose 8 mg cilansetron (TID) and 63% for the dose 16 mg cilansetron(TID). The success rates were very similar for the male and femalepatient groups. The greatest differences were observed for the dose of 1mg cilansetron (TID).

[0021] It can be seen from the data given above that the non-obstipativeIBS patients of both sexes respond to the treatment with cilansetron inall the dosages investigated.

[0022] It is particularly surprising that cilansetron is effective, asproved by the above results of the investigations, in the treatment ofnon-obstipative (=diarrhea-predominant) male IBS patients, since theperson skilled in the art had to conclude from the contents of WO99/17755 that cilansetron, just like alosetron, was preferentiallysuited only for the treatment of non-obstipative female IBS patients.

[0023] Previously-known 5HT₃-receptor antagonists are usuallyadministered twice a day for treatment of IBS (=“BID dosage”). However,it has proved more advantageous for treating IBS patients of both sexesinstead to administer 5HT₃-receptor antagonists three times a day (=“TIDdosage”), for example in doses of 1 mg to 16 mg each time to IBSpatients of both sexes. It is particularly preferred to spread thethrice daily administration of 5HT₃-antagonists across the day and inparticular to prescribe them after main meals (morning, mid-day andevening). Examples of 5HT₃-receptor antagonists which can be moreadvantageously administered in three daily doses include alosetron,azasetron, dolasetron, granisetron, indisetron, itasetron, lerisetron,ondansetron, ramosetron, tropisetron and (R)-Zacopride. It has provedparticularly advantageous for treating IBS patients of both sexes toadminister cilansetron or the pharmacologically acceptable acid additionsalts and/or solvates thereof to the patients three times a day, forexample each time in doses of between 1 mg and 16 mg per administereddose.

[0024] In accordance with the invention, cilansetron or apharmacologically acceptable acid addition salt of cilansetron may becontained as a therapeutic agent, together with conventionalpharmaceutical auxiliaries and/or carriers, in solid or liquidpharmaceutical preparations. Examples of solid preparations arepreparations which can be administered orally, such as tablets, coatedtablets, capsules, powders or granules, or alternatively suppositories.These preparations may contain conventional pharmaceutical inorganicand/or organic carriers, such as talcum, lactose or starch, in additionto conventional pharmaceutical auxiliaries, for example lubricants ortablet disintegrating agents. Liquid preparations such as suspensions oremulsions of cilansetron may contain the usual diluents such as water,oils and/or suspension agents such as polyethylene glycols and the like.Other auxiliaries may additionally be added, such as preservatives,taste correctives and the like.

[0025] Cilansetron or a pharmacologically acceptable acid addition saltof cilansetron can be mixed and formulated with the pharmaceuticalauxiliaries and/or carriers in a known manner. For the production ofsolid medicament forms, cilansetron or an acid addition salt can forexample be mixed with the auxiliaries and/or carriers in a conventionalmanner and can be wet or dry granulated. The granules or powder can bepoured directly into capsules or be pressed into tablet cores in aconventional manner. These can be coated in a known manner if desired.

[0026] The following example is intended to explain the production ofpharmaceutical preparations containing cilansetron hydrochloride.

EXAMPLE 1 Tablets

[0027] Composition: Cilansetron hydrochloride monohydrate  4 parts Cornstarch  30 parts Lactose  70 parts Kollidon 25 ™  5 parts Magnesiumstearate  2 parts Talcum  3 parts Total: 114 parts

[0028] Preparation Procedure:

[0029] The active substance was mixed with corn starch andfinely-powdered lactose in a mixer. The resulting mixture was moistenedthoroughly with a 20% solution of polyvinylpyrrolidone (Kollidon 25™ byBASF) in demineralized water. If necessary, further demineralized waterwas added. The moist granules were passed through a 2 mm sieve, dried ontrays at 40° C. and then passed through a 1 mm sieve (Frewitt machine).After mixing the granules with magnesium stearate and talcum, tablets ofa weight of 114 mg were pressed therefrom, so that each tablet contained4 mg of active substance.

[0030] Likewise, other pharmaceutical preparations of cilansetron, forexample those known from EP 895,782 A2, may be used.

[0031] The foregoing description and examples have been set forth merelyto illustrate the invention and are not intended to be limiting. Sincemodifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations fallingwithin the scope of the appended claims and equivalents thereof.

What is claimed is:
 1. A method of inhibiting preparations for thetreatment and/or prophylaxis of irritable bowel syndrome (=IBS) in anon-obstipative male patient, said method comprising administering tosaid patient a pharmaceutical composition comprising an effective IBSinhibiting amount of cilansetron or a pharmacologically acceptable acidaddition salt thereof or a solvate thereof.
 2. A method according toclaim 1, wherein said pharmaceutical composition comprises cilansetronhydrochloride.
 3. A method according to claim 1, wherein saidpharmaceutical composition comprises cilansetron hydrochloridemonohydrate.
 4. A method of treating a human patient suffering fromirritable bowel syndrome (=IBS), said method comprising administering apharmaceutical composition comprising at least one 5HT₃-receptorantagonist to said patient three times a day.
 5. A method according toclaim 4, wherein said at least one 5HT₃-receptor antagonist isadministered in a dose of from 1 mg to 16 mg.
 6. A method according toclaim 4, wherein the three times daily administration of saidpharmaceutical composition takes place after morning, mid-day andevening meals, respectively.
 7. A method according to claim 4, whereinsaid 5HT₃-receptor antagonist comprises at least one active substanceselected from the group consisting of alosetron, azasetron, dolasetron,granisetron, indisetron, itasetron, lerisetron, ondansetron, ramosetron,tropisetron, and (R)-Zacopride.
 8. A method according to claim 4,wherein said 5HT₃-receptor antagonist comprises cilansetron or apharmacologically acceptable acid addition salt thereof or a solvatesthereof.